Aromatic sulfonamide derivatives, their use as enzyme inhibitors and pharmaceutical compositions containing them

ABSTRACT

Aromatic sulfonamide derivatives, particularly benzenesulfonamide, 4-fluorobenzenesulfonamide, 5-chloro-1-naphthalenesulfonamide and 5-isoquinolinesulfonamide derivatives are provided that inhibit Ca 2+  -dependent enzymes and proteins such as Phospholipase A 2 , protein kinases such as Protein Kinase C, and inhibit membrane fusion, thereby being a valuable drug for the treatment of inflammation, arthritis, infarction, nephritis and many other types of tissue injury.

This is a continuation of application Ser. No. 08/204,317, filed as PCT/EP91/01678 on Sep. 5, 1991, now abandoned.

This invention relates to aromatic sulfonamide derivatives, especially to benzenesulfonamide-, 4-fluorobenzenesulfonamide-, 5-chloro-1-naphthalenesulfonamide- and 5-isoquinolinesulfonamide derivatives.

This invention particularly relates to aromatic sulfonamide derivatives that inhibit Ca²⁺ -dependent enzymes and proteins such as Phospholipase A₂, thereby being a valuable drug for the treatment of inflammation, and provides a process for the preparation thereof.

The aromatic sulfonamide derivatives of this invention potentially have promise for inhibiting protein kinases such as Protein Kinase C, and membrane fusion, thereby possibly being drugs for the treatment of arthritis, infarction, nephritis and many other types of tissue injury.

The invention further relates to pharmaceutical compositions containing these derivatives.

BACKGROUND OF THE INVENTION

Literature pertinent to the invention includes the following documents:

L. Goldman & J. H. Williams, J. Org. Chem., Vol. 18, p. 815 (1953).

W. H. Schuller & C. Niemann, J.A.C.S., Vol. 73, p. 1644 (1951).

T. F. Buckley & H. Rapoport, J.A.C.S., Vol. 103, p. 6157 (1981).

C. G. Knudsen & H. Rapoport, J. Org. Chem., Vol. 48, p. 2260 (1983).

H. Rapoport, et al., J.A.C.S., Vol. 106, p. 1095 (1984).

G. J. Atwell & W. A. Denny, Synthesis, p. 1032 (1984).

G. Skopp & G. Schwenker, Arch. Pharm., Vol. 317, p. 649 (1984).

R. C. Hart, et al., Methods in Enzymology, Vol. 102, p. 195 (1983).

H. Hidaka, European Patent 0187371 (1985).

T. Matsui, et al., J. Soc. Org. Synth. Chem. Japan, Vol. 13, p. 320 (1985).

F. Alonso, et al., Biochim. Biophys. Acta, Vol. 878, p. 273 (1986).

W. C. Ripka, et al., J. Cell. Biochem., Vol. 40, p. 279 (1989).

SUMMARY OF THE INVENTION

The invention relates to compounds of the general formula: ##STR1## wherein Z is phenyl, naphthyl, (5)- or (8)-isoquinolyl, possibly substituted by halogen;

A is an amino acid group where the N atom of the amino acid group is bound to SO₂ and its carboxyl group to the N atom of formula I

R₁ is hydrogen, and

R₂ is phenyl, biphenyl, a C₂ to C₆ -alkylamine or R₁ and R₂ together form the piperazine ring

and its pharmaceutically acceptable non-toxic acid addition salts with inorganic or organic acids.

In another embodiment, the compounds of I have one of the following formulae: ##STR2## wherein A, R₁ and R₂ have the meaning as defined above with respect to formula I,

Y is F, Cl, Br, being the same or different, and

n is 0, 1, or 2.

DETAILED DESCRIPTION

The invention is defined in detail in the claims.

A groups in formulae I-IV particularly include L-phenylalanine, L-alanine, L-proline, L-valine, n-tryptophane and L-tyrosine--where the N atom is bound to the SO₂ group.

When the R₁ group in formulae I-IV is hydrogen, then the R₂ group is benzyl, biphenyl or a C₃ or C₆ alkylene chain. A 6 membered heterocyclic ring (piperazine) may be formed through an ethylene group and adjacent nitrogen atoms.

Exemplary benzenesulfonamide derivatives of the invention include:

(1) N-benzenesulfonyl-L-phenylalanine piperazineamide [referred to as compound 1];

(2) N-benzenesulfonyl-L-alanine piperazineamide [referred to as compound 2];

(3) N-benzenesulfonyl-L-valine piperazineamide [referred to as compound 3];

(4) N-benzenesulfonyl-L-proline piperazineamide [referred to as compound 4];

(5) N-benzenesulfonyl-L-phenylalanine-1,6-diaminohexaneamide [referred to as compound 5];

(6) N-benzenesulfonyl-L-phenylalanine-1,3-diaminopropaneamide [referred to as compound 6];

(7) N-benzenesulfonyl-L-phenylalanine biphenylamide [referred to as compound 7];

(8) N-benzenesulfonyl-L-alanine biphenylamide [referred to as compound 8];

(9) N-benzenesulfonyl-L-valine biphenylamide [referred to as compound 9];

(10) N-benzenesulfonyl-L-proline biphenylamide [referred to as compound 10];

(11) N-benzenesulfonyl-L-tryptophane biphenylamide [referred to as compound 11];

(12) N-benzenesulfonyl-L-tyrosine biphenylamide [referred to as compound 12];

Exemplary 4-fluorobenzenesulfonylamide derivatives of the invention include:

(13) N-(4-fluorobenzenesulfonyl)-L-phenylalanine piperazineamide [referred to as compound 13];

(14) N-(4-fluorobenzenesulfonyl)-L-alanine piperazineamide [referred to as compound 14];

(15) N-(4-fluorobenzenesulfonyl)-L-valine piperazineamide [referred to as compound 15];

(16) N-(4-fluorobenzenesulfonyl)-L-proline piperazineamide [referred to as compound 16];

(17) N-(4-fluorobenzenesulfonyl)-L-phenylalanine biphenylamide [referred to as compound 17];

(18) N-(4-fluorobenzenesulfonyl)-L-alanine biphenylamide [referred to as compound 18];

(19) N-(4-fluorobenzenesulfonyl)-L-valine biphenylamide [referred to as compound 19];

(20) N-(4-fluorobenzenesulfonyl)-L-proline biphenylamide [referred to as compound 20];

Exemplary 5-chloro-1-naphthalenesulfonamide derivatives of the invention include:

(21) N-(5-chloro-1-naphthalenesulfonyl)-L-phenylalanine piperazineamide [referred to as compound 21];

(22) N-(5-chloro-1-naphthalenesulfonyl)-L-valine piperazineamide [referred to as compound 22];

(23) N-(5-chloro-1-naphthalenesulfonyl)-L-proline piperazineamide [referred to as compound 23];

(24) N-(5-chloro-1-naphthalenesulfonyl)-L-alanine piperazineamide [referred to as compound 24];

(25) N-(5-chloro-1-naphthalenesulfonyl)-L-phenylalanine-1,6-diaminohexaneamide [referred to as compound 25];

(26) N-(5-chloro-1-naphthalenesulfonyl)-L-phenylalanine biphenylamide [referred to as, compound 26];

(27) N-(5-chloro-1-naphthalenesulfonyl)-L-alanine biphenylamide [referred to as compound 27];

(28) N-(5-chloro-1-naphthalenesulfonyl)-L-valine biphenylamide [referred to as compound 28];

(29) N-(5-chloro-1-naphthalenesulfonyl)-L-proline biphenylamide [referred to as compound 29];

(30) N-biphenyl-5-chloro-1-naphthalenesulfonamide [referred to as compound 30];

Exemplary 5-isoquinolinesulfonylamide derivatives of the invention include:

(31) N-(5-isoquinolinesulfonyl)-L-phenylalanine piperazineamide [referred to as compound 31];

(32) N-(5-isoquinolinesulfonyl)-L-valine piperazineamide [referred to as compound 32];

(33) N-(5-isoquinolinesulfonyl)-L-proline piperazineamide [referred to as compound 33];

(34) N-(5-isoquinolinesulfonyl)-L-alanine piperazineamide [referred to as compound 34];

(35) N-(5-isoquinolinesulfonyl)-L-phenylalanine-1,6-diaminohexaneamide [referred to as compound 35];

(36) N-(5-isoquinolinesulfonyl)-L-phenylalanine biphenylamide [referred to as compound 36];

(37) N-(5-isoquinolinesulfonyl)-L-valine biphenylamide [referred to as compound 37];

(38) N-(5-isoquinolinesulfonyl)-L-proline biphenylamide [referred to as compound 38];

(39) N-(5-isoquinolinesulfonyl)-L-alanine biphenylamide [referred to as compound 39];

(40) N-(5-isoquinolinesulfonyl)-D-proline biphenylamide [referred to as compound 40];

(41) N-biphenyl-5-isoquinolinesulfonamide [referred to as compound 41];

(42) N-benzyl-5-isoquinolinesulfonamide [referred to as compound 42];

The acid addition salts of the derivatives 1-6, 13-16, 21-25 and 31-35 according to this invention are pharmaceutically acceptable non-toxic salts and can be prepared by conventional methods. Suitable examples of such pharmaceutically acceptable acid addition salts include the salts of inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid; and the salts of organic acids such as acetic acid, citric acid, tartaric acid, lactic acid, succinic acid, fumaric acid, maleic acid, methanesulfonic acid and p-toluenesulfonic acid.

The benzenesulfonamide--and the 4-fluorobenzenesulfonamide derivatives of formula I-II can be prepared in accordance with the following equations: ##STR3## wherein A is a part of an amino acid, R₁ is a hydrogen atom, R₂ is a biphenyl group and R₃ is a hydrogen or a flourine atom;

or ##STR4## wherein A is a part of an amino acid, R₁ is a hydrogen atom and R₂ a C₃ or C₆ alkylene chain; or R₁ and R₂ are linked directly to form a piperazine ring. R₃ is a hydrogen or a flourine atom and X a protective group.

Derivative V can be prepared as follows: ##STR5## wherein AA is an amino acid and R₃ is a hydrogen or a flourine atom.

The naphthalenesulfonylamide derivatives of formula III can be prepared in accordance to the following equations: ##STR6## wherein A is a part of an amino acid or a single bond, R₁ is a hydrogen atom and R₂ is a biphenyl group; or ##STR7## wherein A is a part of an amino acid, R₁ is a hydrogen atom and R₂ a C₆ alkylene chain; or R₁ and R₂ are linked directly to form a piperazine ring. X is a protective group.

Derivative XI can be prepared as follows: ##STR8## wherein AA is an amino acid, R₁ is a hydrogen atom, R₂ a biphenyl group and X a protective group.

Derivative XII can be prepared as follows: ##STR9## wherein AA is an amino acid, R₁ is a hydrogen atom and R₂ a C₆ alkylene chain; or R₁ and R₂ are linked directly to form a piperazine ring. X are protective groups.

The isoquinolinesulfonamide derivatives of formula IV can be prepared in accordance to the following equations: ##STR10## wherein A is a part of an amino acid or a single bond, R₁ is a hydrogen atom and R₂ a phenyl- or biphenyl group; or ##STR11## wherein A is a part of an amino acid, R₁ is a hydrogen atom and R₂ a alkylene chain; or R₁ and R₂ are linked directly to form a piperazine ring. X is a protective group.

Exemplary compounds of formula V include N-benzenesulfonyl-L-phenylalanine, N-benzenesulfonyl-L-alanine, N-benzenesulfonyl-L-valine, N-benzenesulfonyl-L-proline, N-benzenesulfonyl-L-tryptophane and N-benzenesulfonyl-L-tyrosine; N-(4-fluorobenzenesulfonyl)-L-phenylalanine, N-(4-fluorobenzenesulfonyl)-L-alanine, N-(4-fluorobenzenesulfonyl)-L-valine, N-(4-fluorobenzenesulfonyl)-L-proline.

Exemplary compounds of formula VI include 4-aminobiphenyl and 4-aminobenzyl.

Exemplary compounds of formula VII include N-CBZ-piperazine, N-BOC-1,6-diaminohexane and N-CBZ-1,3-diaminopropane.

Exemplary compounds of formula XI include L-phenylalanine biphenylamide, L-alanine biphenylamide, L-valin biphenylamide, L-prolin biphenylamide and D-proline biphenylamide.

Exemplary compounds of formula XII include L-phenylalanine-N-CBZ-piperazineamide, L-alanine-N-CBZ-piperazineamide, L-valine-N-CBZ-piperazineamide and L-phenylalanine-N-BOC-1,6-diaminohexaneamide.

The reaction between the compound of formula V with the compound of formulae VI, or VII is best carried out in presence of dicyclohexylcarbodiimide (DCC) and a reaction medium like dimethylformamide (DMF) or dioxane; 1-hydroxybenzotriazole is used to avoid racemization.

The amount of the compound of formula V preferably is the same as of the compound of formula VI or VII.

The amount of DCC is preferably about 1 to 5 equivalents and more preferably 1 to about 2 equivalents for each mol of the compound of formulae V.

The amount of 1-hydroxybenzotriazole is preferably about 1 to 5 equivalents and more preferably 1 to about 2 equivalents for each mol of the compound of formulae V.

The reaction between the compound of formulae V with VI or VII, respectively, can be carried out typically at a temperature of about -10° C. to about 60° C. and preferably from about 0° C. to 30° C.

The reaction time which can be employed is typically about 1 h to about 24 h and preferably from 1 h to about 5 h.

The method of obtaining the compounds of formulae I and II from VIII may vary depending upon the protective group of X selected, generally known methods can be employed in this invention. For example when the protective group of X is an alkyloxycarbonyl group such as t-butoxycarbonyl, the desired products can be obtained by hydrolysis with an acid. When the promotive group of X is an arylmethyloxycarbonyl group such as benzyloxycarbonyl, the desired compounds can be obtained by hydrogenation or hydrolysis with an acid.

The reaction between the compound of formulae X with XI or XII respectively is best carried out in presence of an acid acceptor. Exemplary acid acceptors which can be employed include alkali metal compounds such as hydroxide, bicarbonate or carbonate, e.g. sodium hydroxide, potassium hydroxide, sodium bicarbonate, sodium carbonate, potassium carbonate and tertiary amines such as triethylamine and pyridine.

In general the reaction is carried out in presence of a reaction medium. Exemplary reaction media which can be employed include ethers, such as dioxane or THF and halogenated hydrocarbons such as CHCl₃ and CH₂ Cl₂.

The amount of the compound of formula X preferably is the same as of the compounds of formula XI or XII.

The amount of the acid acceptor employed is preferably about 2 to 5 equivalents with more preferably about 2 to 3 equivalents for each mol of the compound of formulae X.

The reaction between the compound of formulae X with XI or XII respectively can be carried out typically at a temperature of about 10° C. to about 60° C. and preferably at 20° C. to 30° C.

The reaction time which can be employed is typically about 1 h to about 24 h and preferably from 1 h to about 5 h.

The method of obtaining the compound of formula III from XIII can be carried out under the same conditions as the reaction from the compound of formula VIII to the compound of formula I and II.

The reaction between the compound of formulae XVII or XI XII respectively can be carried out under the same condition as the reaction between the compound of formula X and XI respectively XII except that the amount of the compound of formula XVII preferably is 0.9 equivalents of the compound of formula XI respectively XII and that the reaction temperature is preferably of about 0° C. to 30° C.

It has now been found that the derivatives of formulae I-IV (and their pharmaceutically acceptable salts if applicable have pharmacologically and biochemically interesting properties such as Phospholipase A₂ (PLA₂) inhibition activity. The effect of the derivatives of formulae I-IV of this invention on PLA₂ can be proved in vitro by taking bovine pancreatic PLA₂, 1-stearoyl-2-[C¹⁴ ]-arachidonyl-1-phosphatidylcholine and CaCl₂ and adding a derivative of the formulae I-V resulting in inhibition of the PLA₂. When for example N-(5-chloro-1-naphthalenesulfonyl)-L-phenylalanine-1,6-diaminohexaneamide, i.e. compound 25 was added and a complete inhibition was designed 100%, the concentration which would bring about an inhibition of 50%, i.e. IC₅₀ was 67 μM.

The following examples illustrate the present invention in more detail, but they are given for illustrative purposes only and are not to be construed as limiting the invention.

Synthesis of the Precursors EXAMPLE 1

Equimolar amounts of O-benzyl-L-tyrosine and benzenesulfonyl chloride were mixed in 1N NaOH (200 mol %) and stirred for 2 h. After 0.5 h the desired compound precipitated. The solution was adjusted to pH 2 with 2N HCl and filtered. The precipitate was washed several times with H₂ O, dried in vacuo over P₂ O₅ and crystallized to yield the desired compound P1.

Substantially the used in place of described above was repeated except that L-tryptophane was used in place of the L-tyrosine derivative to give P2.

The yields of the reactions and the analytical data of the two compounds are given in table 1.

EXAMPLE 2

Equimolar mounts of L-phenylalanine and p-fluorobenzenesulfonyl chloride were mixed in 1N NaOH (200 mol %) and stirred at 60° C. for 2 h. The solution was adjusted to pH 2 with 2N HCl and extracted with EtOAc. The organic phase was dried over MgSO₄, filtered, evaporated and the residue crystallized to yield P3.

Substantially the same procedure as described above was repeated except that L-alanine (→P4), L-valine (→P5) and L-proline (→P6) were used in place of L-phenylalanine.

The yields of the reactions and the analytical data of the different compounds are given in table 1.

EXAMPLE 3

To equimolar amounts of N-t-BOC-L-phenylalanine and 4-aminobiphenyl in DMF (ca 0.5M) 1-hydroxybenzotriazole (150 mol %) was added. The mixture was cooled to 0° C. and DCC (110 mol %) was added in one portion. After stirring for 1 h at 0° C. and 1 h at 25° C. the reaction mixture was filtered and the DMF evaporated in vacuo. The residue was taken up in EtOAc (ca 0.1M) and washed subsequently with saturated NaHCO₃ solution, 2N citric acid and H₂ O. After drying over MgSO₄, filtering and evaporation the residue was crystallized.

The compound obtained above was dissolved in CH₂ Cl₂ (ca 0.4M) cooled with ice and the same amount of TFA added. After 1 h the solvents were evaporated and the residue crystallized: P7.

Substantially the same procedure as described above was repeated except that N-t-BOC-L-valine (→P8) was used in place of the L-phenylalanine derivative. When N-CBZ-L-proline was used as starting material the deprotection was done by overnight hydrogenation with H₂, 10% Pd/C in EtOH (→P9). In case of N-t-BOC-L-alanine the free amine was obtained after evaporation of the solvents and stirring the residue with saturated NaHCO₃ solution (→P10).

The yields of the reactions and the analytical data of the different compounds are given in table 2.

EXAMPLE 4

Basically the same procedure as in example 3 except that N-CBZ-piperazine [1] and N-BOC-6-aminohexane were used in place of 4-aminobiphenyl. In case of N-CBZ-piperazine N-t-BOC protected amino acids and in case of N-t-BOC-6-aminohexane N-CBZ protected amino acids were used.

Deprotection of the N-t-BOC group was done as described before with TFA/CH₂ Cl₂ at 0° C. (→P11,P12,P13,P14) and of the N-CBZ group with H₂, 10% Pd/C in EtOH (→P15,P16). The free amine was dissolved in acetone, equimolar amounts of oxalic acid in acetone added, the precipitate filtered and crystallized.

The yields of the reactions and the analytical data of the different compounds are given in table 2.

Synthesis of the Compounds EXAMPLE 5

To equimolar amounts of N-benzenesulfonyl-L-phenylalanine, [2] and N-CBZ-piperazine [1] in DMF (ca 0.5M) 1-hydroxybenzotriazole (150 mol %) was added. The mixture was cooled to 0° C. and DCC (110 mol %) was added in one portion. After stirring for 1 h at 0° C. and 1 h at 25° C. the reaction mixture was filtered and the DMF evaporated in vacuo. The residue was taken up in EtOAc (ca 0.1M) and washed subsequently with saturated NaHCO₃ solution, 2N citric acid and H₂ O. After drying over MgSO₄, filtering and evaporation of the solvent the residue was crystallized (P17).

The compound obtained above was dissolved in abs. EtOH (ca 0.1M), 10% Pd/C (10 weight %) added and stirred overnight in a H₂ atmosphere. The reaction mixture was filtered over celite and the pH of the solution adjusted to 2 with conc. HCl. Evaporation of the solvent yielded a white residue which was crystallized: 1.

Substantially the same procedure as described above was repeated except that N-benzenesulfonyl-L-alanine [3](→2), N-benzenesulfonyl-L-valine [4](→P18 →3) and N-benzenesulfonyl-L-proline [5](→P19→4) were used in place of N-benzenesulfonyl-L-phenylalanine.

The yields of the reactions and the analytical data of the different compounds are given in table 3 (intermediates) and table 4 and 8 (compounds).

EXAMPLE 6

Basically the same procedure as in example 5 except that N-t-BOC-6-aminohexane (→P20→53) or N-CBZ-aminopropane [6](→P21→6) were used in place of N-CBZ-piperazine. Deprotection of the N-t-BOC group was done with TFA/CH₂ Cl₂ at 0° C. and of the N-CBZ group with H₂, 10% Pd/C in EtOH as described before.

The yields of the reactions and the analytical data of the two compounds are given in table 3 (intermediates) and table 4 and 9 (compounds).

EXAMPLE 7

To equimolar mounts of N-benzenesulfonyl-L-phenylalanine [2] and 4-aminobiphenyl in DMF (ca 0.5M) 1-hydroxybenzotriazole (150 mol %) was added. The mixture was cooled to 0° C. and DCC (110 mol %) was added in one portion. After stirring for 1 h at 0° C. and 1 h at 25° C. the reaction mixture was filtered and the DMF evaporated in vacuo. The residue was taken up in EtOAc (ca 0.1M) and washed subsequently with saturated NaHCO₃ solution, 2N citric acid and H₂ O. After drying over MgSO₄, filtering and evaporation of the solvent the residue was crystallized: 7.

Substantially the same procedure as described above was repeated except that N-benzenesulfonyl-L-alanine [3](→8), N-benzenesulfonyl-L-valine [4](→9), N-benzenesulfonyl-L-proline [5](→10) and N-benzenesulfonyl-L-tryptophane P2 (→11) were used in place of N-benzenesulfonyl-L-phenylalanine.

The yields of the reactions and the analytical data of the different compounds are given in table 4,10,11 and 12.

EXAMPLE 8

Basically the same procedure as in example 7 except that O-benzyl-N-benzenesulfonyl-L-tyrosine P1 was used in place of N-benzenesulfonyl-L-phenylalanine (→P22).

The compound obtained above was dissolved in p-dioxane/H₂ O/HOAc 15:1:1 (ca 10 mM), 10% Pd/C (10 weight %) added and the mixture stirred overnight in a H₂ atmosphere. The reaction mixture was filtered over celite and the solvents evaporated in vacuo. The residue was crystallized: 12.

The yields of the reactions and the analytical data of the two compounds are given in table 3 (intermediate) and table 4 and 10 (compound).

EXAMPLE 9

To equimolar amounts of N-p-fluorobenzenesulfonyl-L-phenylalanine P3 and N-CBZ-piperazine in DMF (ca 0.5M) 1-hydroxybenzotriazole (150 mol %) was added. The mixture was cooled to 0° C. and DCC (110 mol %) was added in one portion. After stirring for 1 h at 0° C. and 1 h at 25° C. the reaction mixture was filtered and the DMF evaporated in vacuo. The residue was taken up in EtOAc (0.1M) and washed subsequently with saturated NaHCO₃ solution, 2N citric acid and H₂ O. After drying over MgSO₄, filtering and evaporation of the solvent the residue was crystallized: P23.

The compound obtained above was dissolved in abs. EtOH (ca 0.1M) 10% Pd/C (10 weight %) added and the mixture stirred overnight in a H₂ atmosphere. The reaction mixture was filtered over celite and the pH of the solution adjusted to 2 with cone. HCl. Evaporation of the solvent yielded a white residue which was crystallized: 13.

Substantially the same procedure as described above was repeated except that N-p-fluorobenzenesulfonyl-L-alanine P4 (→P24→14), N-p-fluorobenzenesulfonyl-L-valine P5 (→P25→15) and N-p-fluorobenzenesulfonyl-L-proline P6 (→P26→16) were used in place of P3.

The yields of the reactions and the analytical data of the different compounds are given in table 3 (intermediates) and 5 and 13 (compounds).

EXAMPLE 10

To equimolar amounts of N-p-fluorobenzenesulfonyl-L-phenylalanine P3 and 4-aminobiphenyl in DMF (ca 0.5M) 1-hydroxybenzotriazole (150 mol %) was added. The mixture was cooled to 0° C. and DCC (110 mol %) was added, in one portion. After stirring for 1 h at 0° C. and 1 h at 25° C. the reaction mixture was filtered and the DMF evaporated in vacuo. The residue was taken up in EtOAc (ca 0.1M) and washed subsequently with saturated NaHCO₃ solution, 2N citric acid and H₂ O. After drying over MgSO₄, filtering and evaporation of the solvent the residue was crystallized: 17.

Substantially the same procedure as described above was repeated except that N-p-fluorobenzenesulfonyl-L-alanine P4 (→18), N-p-fluorobenzenesulfonyl L-valine P5 (→19) and N-p-fluorobenzenesulfonyl L-proline P6 (→20) were used in place of P3.

The yields of the reactions and the analytical data of the different compounds are given in table 5 and 14.

EXAMPLE 11

To a concentrated solution of the amine P11 in p-dioxane and 1N NaOH (200 mol %) an equimolar amount of 5-chloro-1-naphthalenesulfonyl chloride [7,8] was added and the suspension stirred for 3 h. Acidification with conc. HCl to pH 2, extraction with CH₂ Cl₂ (3x), washing of the organic phase once with brine, drying over MgSO₄, filtering and evaporation of the solvents in vacuo yielded a residue which was purified by flash chromatography on silica gel (solvent system hexane/EtOAc 1:1).

The compound obtained above was dissolved in abs. EtOH (ca 50 mM) 10% Pd/C (10 weight %) added and the mixture stirred for 3 days in a H₂ atmosphere. The reaction mixture was filtered over celite, the solvent evaporated in vacuo, the residue purified by flash chromatography on silica gel (solvent system CH₂ Cl₂ /MeOH 5:1) and crystallized: 21.

Substantially the same procedure as described above was repeated except that the amine P12 (→22)², P13 (→23)³ or P14 (→24)⁴ were used in place of the amine P11.

The yields of the reactions and the analytical data of the different compounds are given in table 6 and 15.

EXAMPLE 12

To a concentrated solution of the amine P15 in p-dioxane and 1N NaOH (200 mol %) an equimolar amount of 5-chloro-1-naphthalenesulfonyl chloride was added and the suspension stirred for 3 h. H₂ O was added and the mixture extracted thrice with CH₂ Cl₂. The organic phase was washed once with H₂ O, dried over MgSO₄, filtered and the solvents evaporated in vacuo. Flash chromatography on silica gel (solvent system hexane/EtOAc 1:2) yielded the pure intermediate which was dissolved in CH₂ Cl₂ (ca 50 mM) and the same volume of TFA added. After 1 h the solvents were evaporated in vacuo, the residue dissolved in a small volume of H₂ O and the pH of the solution adjusted to 8 with solid NaHCO₃. Extraction with four portions of CH₂ Cl₂ /MeOH 3:1, washing of the organic phase with H₂ O, drying over MgSO₄, filtering and evaporation of the solvents in vacuo yielded a compound which was purified by flash chromatography on silica gel (solvent system CH₂ Cl₂ /MeOH/conc.NH₃ 20:2:1) and crystallized as HCl-salt 25.

The yield of the reaction and the analytical data of the compound are given in table 6 and 16.

EXAMPLE 13

To a concentrated solution of the amine P7 in THF and 1N NaOH (200 mol %) an equimolar amount of 5-chloro-1-naphthalenesulfonyl chloride was added and the suspension stirred for 3 h. H₂ O was added and the mixture extracted thrice with CH₂ Cl₂. The organic phase was washed once with H₂ O, dried over MgSO₄, filtered and the solvents evaporated in vacuo. Flash chromatography on silica gel (solvent system hexane/EtOAc 4:1) and crystallization yielded the pure compound 26.

Substantially the same procedure as described above was repeated except that the amine P10 (→27)⁵ was used in place of the amine P7.

The yields of the reactions and the analytical data of the two compounds are given in table 6 and 17.

EXAMPLE 14

To a concentrated solution of the amine P8 in p-dioxane was added 1N NaOH (200 mol %). The precipitate partly dissolved after addition of a concentrated solution of an equimolar mount of 5-chloro-1-naphthalenesulfonyl chloride in THF. After 15 min. the desired compound precipitated. After 2 h H₂ O was added and the suspension filtered, the solid dried and crystallized twice to obtain the pure compound 28.

Substantially the same procedure as described above was repeated except that the amine P9 (→29) was used in place of the amine P8.

The yields of the reactions and the analytical data of the two compounds are given in table 6 and 17.

EXAMPLE 15

To a concentrated solution of 4-aminobiphenyl in p-dioxane was added 1N NaOH (200 mol %) and an equimolar amount of 5-chloro-1-naphthalenesulfonyl chloride. After stirring for 2 h the solvents were evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent system hexane/EtOAc 2:1) and crystallized to yield 30.

The yield of the reaction and the analytical data of the compound are given in table 6 and 17.

EXAMPLE 16

To an ice cooled suspension of 5-isoquinolinesulfonyl chloride hydrochloride [9] in CH₂ Cl₂ was added NEt₃ (220 mol %). To the yellow solution the amine P11 (90 mol %) in CH₂ Cl₂ was added dropwise. After 10 min. the cooling was removed and the stirring continued for 2 h. The pH of the solution was adjusted to 7-8 with a saturated NaHCO₃ solution. The phases were separated and the organic phase washed once with H₂ O, dried over MgSO₄, filtered and the solvent evaporated in vacuo. Flash chromatography on silica gel (solvent system CH₂ Cl₂ /MeOH 100:3) yielded a white foam.

A solution of the compound obtained above in 25% HBr/HOAc (8 ml/mmol) was stirred under ice cooling for 5 h. After addition of Et₂ O (ca 40 ml/mmol the precipitate was filtered and dissolved in a few ml of H₂ O. The solution was slightly basified with 1N NaOH and extracted with CH₂ Cl₂ /MeOH 3:1 (4x). The organic phase was washed once with H₂ O, dried over MgSO₄, filtered and the solvents evaporated in vacuo. Flash chromatography on silica gel (solvent system CH₂ Cl₂ /MeOH/conc. NH₃ 20:4:1) yielded a foam which was dissolved in EtOH and treated with cone. HCl to give the salt 31.

Substantially the same procedure as described above was repeated except that the amine P12 (→32)⁶,7 P13 (→33) and P14 (→34)⁸,9 were used in place of the amine P11.

The yields of the reactions and the analytical data of the different compounds are given in table 7 and 18.

EXAMPLE 17

To an ice cooled suspension of 5-isoquinolinesulfonyl chloride hydrochloride in CH₂ Cl₂ was added NEt₃ (220 mol %). To the yellow solution the amine P15 (90 mol %) in CH₂ C₂ was added dropwise. After 10 min. the cooling was removed and stirring continued for 2 h. A saturated NaHCO₃ solution was added to adjust the pH to 7-8. The phases were separated and the organic phase washed once with H₂ O, dried over MgSO₄, filtered and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel (solvent system CH₂ Cl₂ /MeOH 100:4).

To the compound obtained above, dissolved in CH₂ Cl₂ (ca 50 mM), the same volume of TFA was added. After 1 h the solvents were evaporated in vacuo, the residue dissolved in a very small volume of H₂ O and the pH of the solution adjusted to 8 with solid NaHCO₃. The H₂ O phase was extracted with CH₂ Cl₂ /MeOH 3:1 (4x). The organic phase was dried over MgSO₄, filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (solvent system CH₂ Cl₂ /MeOH/conc. NH₃ 20:4:1) and crystallized as HCl-salt 35.

The yield of the reaction and the analytical data of the compound are given in table 7 and 16.

EXAMPLE 18

To an ice cooled suspension of 5-isoquinolinesulfonyl chloride hydrochloride in CH₂ Cl₂ was added NEt₃ (220 mol %). To the yellow solution the amine P7 (90 mol %) was added dropwise. After 10 min. the cooling was removed and stirring continued for 2 h. The pH of the solution was adjusted to 7-8 with a saturated NaHCO₃ solution. The phases were separated and the organic phase washed once with H₂ O, dried over MgSO₄, filtered and the solvent evaporated in vacuo. Flash chromatography on silica gel (solvent system CH₂ Cl₂ /MeOH 100:3) yielded a white solid which was crystallized to give 36.

Substantially the same procedure as described above was repeated except that the amine P8 (→37), P9 (→38)¹⁰, P10 (→39)¹¹ and (+)-P9 (→40) were used in place of the amine P7.

The yields of the reactions and the analytical data of the different compounds are given in table 7 and 19.

EXAMPLE 19

Substantially the same procedure as described in example 18 was used except that 4-aminobiphenyl (→41)¹² and 4-aminobenzol (→42) were used in place of the amine P7.

The yields of the reaction and the analytical data of the two compounds are given in table 7 and 19.

Enzyme Assay

Phospholipase A₂ (PLA₂) activity was measured using bovine pancreatic PLA₂ as the enzyme and a sonicated dispersion of 1-stearoyl-2-[C¹⁴ ]-arachidonyl-phosphatidylcholine (56 mCi/mmol) as the substrate in the following manner [11,12]: 60 ng bovine pancreatic PLA₂ was mixed and incubated with buffer and inhibitors (100 mM Tris, pH 8; 100 mM CaCl₂ ; 20 mM EDTA, pH 8) at 37° C. for 10 min. to allow interaction between the enzyme and the drugs. The substrate (38 nCi) in buffer and 0.3% cholate was added to initiate the reaction which continued for 20 min. at 37° C. The total reaction volume was 0.1 ml. The reaction was stopped by adding 0.1 ml of an ice cold EtOH/HOAc 98:2 mixture. Released arachidonic acid was separated from the unreacted substrate via thin layer chromatography on silica gel (solvent system CHCl₃ /MeOH/H₂ O 14:6:1). The radioactivity of the two spots was quantified using a bioscanner.

Inhibitors were dissolved in buffer¹³ and tested in duplicate within each experiment, and each inhibitor was tested in at least two experiments. When necessary, inhibitors were dissolved in DMSO¹⁴. The % inhibition at a given concentration was combined for several experiments and the IC₅₀ determined from a semilog plot of % inhibition vs concentration. Under the condition described the rate of hydrolysis was 20-25% of the substrate being hydrolyzed in absence of inhibitors. The results are listed in table 20.

                                      TABLE 1                                      __________________________________________________________________________                                   mp, [°C.]                                                                               yield     MS, m/e                                              (cryst. from)                                                                         [α].sub.D.sup.20,                                                                 [%]egree.]                                                                        analysis                                                                              [%]  ID                __________________________________________________________________________      ##STR12##                                                                                  ##STR13##        150-151 (EtOH)                                                                        +0.27 (c = 1.11, acetone)                                                               63.5                                                                              C.sub.22 H.sub.21                                                              NO.sub.5 S *0.5 H.sub.2                                                        O *0.5                                                                                411                                                                                 P19)H,N)                       ##STR14##        153-154 (EtOH)                                                                        +36.5 (C = 1.07, DMSO)                                                                  50.1                                                                              C.sub.17 H.sub.16                                                              N.sub.2 O.sub.4 S                                                                     344                                                                                 P27)               ##STR15##                                                                                  ##STR16##        118-119 (Et.sub.2 O, pet.                                                             +5.8 (c = 1.18, EtOH)                                                                   57.8                                                                              C.sub.15 H.sub.14                                                              FNO.sub.4 S (C,H,N)                                                                   323                                                                                 P3.1)                          ##STR17##        109-110 (Et.sub.2 O, pet.                                                             -3.9 (c = 1.42, EtOH)                                                                   58.9                                                                              C.sub.9 H.sub.10                                                               FNO.sub.4 S (C,H,N)                                                                   247                                                                                 P4.1)                          ##STR18##        126-127 (Et.sub.2 O, pet.                                                             +23.1 (c = 1.43, EtOH)                                                                  64.5                                                                              C.sub.11 H.sub.14                                                              FNO.sub.4 S (C,H,N)                                                                   275                                                                                 P5)                            ##STR19##        116-117 (Et.sub.2 O, pet.                                                             -81.9 (c = 1.5, EtOH)                                                                   77.3                                                                              C.sub.11 H.sub.12                                                              FNO.sub.4 S (C,H,N)                                                                   273                                                                                 P6.1)             __________________________________________________________________________

                                      TABLE 2                                      __________________________________________________________________________                                       mp, [°C.]  yield                                                     R  (cryst. from)                                                                           [α].sub.D.sup.20,                                                        [°]                                                                              [%]                        __________________________________________________________________________      ##STR20##                                                                                    ##STR21##       BOC                                                                               186-187 (acetone)                                                                       -6.9 (c = 0.62,                                                                         66.4.sub.3)                 ##STR22##                     H  213-214 (acetone, Et.sub.2 O, pet.                                             ether)   +15.1 (c = 0.69,                                                                        72.5one)                    ##STR23##                     BOC                                                                               180-182 (EtOAc, hexane)                                                                 -33.3 (c = 0.91,                                                                        58.3.sub.3)                                               H  190-191 (EtOH, pet. ether)                                                              -71.4 (c = 0.57,                                                                        67.5one)                    ##STR24##                     H  156-157 (EtOH)                                                                          -54.0 (c = 0.79,                                                                        54.7.sub.3)                 ##STR25##                     BOC                                                                               159-160 (EtOAc)                                                                         -63.1 (c = 1.1,                                                                         69.6.sub.3)                                               H  217-218 (MeOH)                                                                          +7.5 (c = 0.27,                                                                         100O)                       ##STR26##                                                                                    ##STR27##       H  181-183 (EtOH)                                                                          +26.9 (c = 0.525,                                                                       58.1)                       ##STR28##                     BOC                                                                               104-105 (acetone, pet.                                                                  +27.1 (c = 0.95,                                                                        65.1.sub.3)                                               H  153-154  +17.3    78.2                                                         (acetone)                                                                               (c = 1.04, H.sub.2 O)                ##STR29##                     BOC                                                                               109-110 (acetone, pet.                                                                  -9.7 (c = 0.65,                                                                         84.6.sub.3)                                               H  141-142  -21.6    81.3                                                         (EtOH)   (C = 0.58, acetone)                  ##STR30##                     H  193-194 (MeOH)                                                                          +4.9 (c = 0.88,                                                                         79.7)                       ##STR31##    ...HN(CH.sub.2).sub.6 NHBOC                                                                     CBZ                                                                               126-127 (acetone)                                                                       +4.5 (c = 1.15,                                                                         57.4.sub.3)                                               H  142-143  +31.9    100                                                          (EtOH)   (c = 0.74, MeOH)                     ##STR32##                     CBZ                                                                               95-96 (acetone)                                                                         -56.9 (c = 1.2,                                                                         67.7.sub.3)                                               H  163-164  -25.1    85.0                                                         (EtOH)   (c = 0.71, DMSO)                    __________________________________________________________________________                                      analysis    MS, m/e [%]                                                                           ID                         __________________________________________________________________________      ##STR33##                                                                                     ##STR34##        C.sub.26 H.sub.28 N.sub.2 O.sub.3                                              (C,H,N)     416 (24)                                                           C.sub.21 H.sub.20 N.sub.2 O                                                                316 (9)                                                                               P7                                                          *CF.sub.3 COOH                                                                 (C,H,N)                                        ##STR35##                       C.sub.22 H.sub.28 N.sub.2 O.sub.3                                              (C,H,N)     368 (0.2)                                                          C.sub.17 H.sub.20 N.sub.2 O                                                                268 (10)                                                                              P8                                                          *CF.sub.3 COOH                                                                 (C,H,N)                                        ##STR36##                       C.sub.17 H.sub.18 N.sub.2 O                                                                266 (42)                                                                              P9                          ##STR37##                       C.sub.20 H.sub.24 N.sub.2 O.sub.3                                              (C,H,N)     340 (0.2)                                                          C.sub.15 H.sub.16 N.sub.2 O                                                                240 (13)                                                                              P10                                                         *(COOH).sub.2 *0.25 MeOH                                                       (C,H,N)                                        ##STR38##                                                                                     ##STR39##        C.sub.21 H.sub.25 N.sub.3 O.sub.3 *0.75                                        (COOH).sub.2 (C,H,N)                                                                       367 (0.1)                                                                             P11                         ##STR40##                       C.sub.22 H.sub.33 N.sub.3 O.sub.5                                              (C,H,N)     419 (0.1)                                                          C.sub.17 H.sub.25 N.sub.3 O.sub.3                                                                 P12                                                         *0.5(COOH).sub.2                               ##STR41##                       C.sub.22 H.sub.31 N.sub.3 O.sub.5                                              (C,H,N)     417 (0.3)                                                          C.sub.17 H.sub.23 N.sub.3 O.sub.3                                                                 P13                                                         *(COOH).sub.2                                                                  (C,H,N)                                        ##STR42##                       C.sub.15 H.sub.21 N.sub.3 O.sub.3                                              *(COOH).sub.2  (C,H,N)                                                                            P14                         ##STR43##                       C.sub.28 H.sub.39 N.sub.3 O.sub.5                                              (C,H,N)     497 (0.1)                                                          C.sub.20 H.sub.33 N.sub.3 O.sub.3                                                                 P15                                                         *(COOH).sub.2 *0.3 H.sub.2 O                                                   (C,H,N)                                        ##STR44##                       C.sub.24 H.sub.37 N.sub.3 O.sub.5                                              (C,H,N)     447 (0.2)                                                          C.sub.16 H.sub.31 N.sub.3 O.sub.3                                                                 P16                                                         *(COOH).sub.2                                                                  (C,H,N)                                       __________________________________________________________________________

                                      TABLE 3                                      __________________________________________________________________________                                                    mp, [°C.]                                                               (cryst. form)                                                                         [α].sub.D.sup.                                                           20,                      __________________________________________________________________________                                                           [°]                ##STR45##                                                                                  ##STR46##                                                                                        ##STR47##       116-117 (EtOH, pet.                                                                   +81.2 (c = 1.08,                                                               CHCl.sub.3)                           ##STR48##                         119-120 (EtOH)                                                                        +77.6 (c = 1.0,                                                                CHCl.sub.3)                           ##STR49##                         158-160 (EtOH)                                                                        -29.0 (c = 1.0,                                                                CHCl.sub.3)                           ##STR50##        ...HN(CH.sub.2).sub.6 NHBOC                                                                     154-155 (acetone)                                                                     +18.0 (c = 0.56,                                                               DMSO)                                                  ...HN(CH.sub.2).sub.3 NHCBZ                                                                     135-136                                                                               -24.7                                                                   (acetone,                                                                             (c = 0.785,                                                                    CHCl.sub.3)                                                             ether)                                       ##STR51##                                                                                        ##STR52##       211-212 (acetone)                                                                     +81.9 (c = 0.81,                                                               DMSO)                     ##STR53##                                                                                  ##STR54##                                                                                        ##STR55##       104-105 (EtOH, pet.                                                                   +73.0 (c = 1.22,                                                               CHCl.sub.3)                           ##STR56##                         97-98 (EtOH,                                                                          +36.8 (c = 0.86,                                                               CHCl.sub.3)                           ##STR57##                         156-157 (EtOH)                                                                        -12.0 (C = 1.4,                                                                CHCl.sub.3)                           ##STR58##                         102-103 (t-amylalcohol)                                                               +63.7 (c = 0.56,                                                               DMSO)                    __________________________________________________________________________                                                              MS,                                                                  yield     m/e                                                                  [%]                                                                               analysis                                                                              [%]                                                                               ID                 __________________________________________________________________________      ##STR59##                                                                                  ##STR60##                                                                                        ##STR61##       82.0                                                                              C.sub.27 H.sub.29                                                              N.sub.3 O.sub.5 S                                                              (C,H,N)                                                                               507 (1)                                                                           P17                             ##STR62##                         81.0                                                                              C.sub.23 H.sub.29                                                              N.sub.3 O.sub.5 S                                                              (C,H,N)                                                                               459 (1)                                                                           P18                             ##STR63##                         44.0                                                                              C.sub.23 H.sub.27                                                              N.sub.3 O.sub.5 S                                                              (C,H,N)                                                                               457 (1)                                                                           P19                             ##STR64##        ...HN(CH.sub.2).sub.6 NHBOC                                                                     81.5                                                                              C.sub.26 H.sub.37                                                              N.sub.3 O.sub.5                                                                       503 (6)                                                                           P20                                              ...HN(CH.sub.2).sub.3 NHCBZ                                                                     59.0                                                                              C.sub.26 H.sub.29                                                              N.sub.3 O.sub.5 S                                                              (C,H,N)                                                                               495 (0.1)                                                                         P21                             ##STR65##                                                                                        ##STR66##       59.9                                                                              C.sub.34 H.sub.30                                                              N.sub.2 O.sub.4 S                                                              (C,H,N)                                                                               562 (12)                                                                          P22                 ##STR67##                                                                                  ##STR68##                                                                                        ##STR69##       86.1                                                                              C.sub.27 H.sub.28                                                              FN.sub.3 O.sub.5 S                                                             (C,H,N)                                                                               525 (0.3)                                                                         P23                             ##STR70##                         79.7                                                                              C.sub.21 H.sub.24                                                              FN.sub.3 O.sub.5 S *0.5                                                        C.sub.6 H.sub.14                                                               (C,H,N)                                                                               449 (4)                                                                           P24                             ##STR71##                         66.5                                                                              C.sub.23 H.sub.26                                                              FN.sub.3 O.sub.5 S                                                             (C,H,N)                                                                               475 (0.1)                                                                         P25                             ##STR72##                         71.0                                                                              C.sub.23 H.sub.28                                                              FN.sub.3 O.sub.5 S                                                             *0.25 t-amyl- alcohol                                                          (C,H,N)                                                                               477 (28)                                                                          P26                __________________________________________________________________________

                                      TABLE 4                                      __________________________________________________________________________                                                 mp, [°C.]                                                                               yield                                                          (cryst. from)                                                                         [α].sub.D.sup.20,                                                         [°]                                                                             [%]                __________________________________________________________________________      ##STR73##                                                                                ##STR74##                                                                                       ##STR75##       231-233 (MeOH,Et.sub.2                                                                +63.3 (c = 2.095,                                                              H.sub.2 O)                                                                              81.5                          ##STR76##                        203-204 (EtOH, Et.sub.2                                                               -4.7 (c = 0.725,                                                               H.sub.2 O)                                                                              80.1                          ##STR77##                        248-250 (EtOH, Et.sub.2                                                               +34.3 (c = 1.515,                                                              H.sub.2 O)                                                                              58.1                          ##STR78##                        282-284 dec (EtOH)                                                                    -135.6 (c = 1.72,                                                              H.sub.2) 78.8                          ##STR79##       ...HN(CH.sub.2).sub.6 NH.sub.2                                                                  123-124 (MeOH, Et.sub.2                                                               +0.1 (c = 0.955,                                                               H.sub.2 O)                                                                              81.0                                          ...HN(CH.sub.2).sub.3 NH.sub.2                                                                  150-152;                                                                              -42.6    81.0                                                           sinters at ca                                                                         (c = 0.655, EtOH)                                                       80°                                                                     (amorphous)                         ##STR80##                                                                                ##STR81##                                                                                       ##STR82##       200-202 (EtOH)                                                                        +15.4 (c = 0.62,                                                               acetone) 72.4                          ##STR83##                        178-180 (EtOH)                                                                        -75.6 (c = 0.6,                                                                acetone) 55.5                          ##STR84##                        226-227 (EtOH)                                                                        -12.7 (c = 0.94,                                                               acetone) 54.4                          ##STR85##                        212-214 (EtOH)                                                                        -224.0 (c = 0.26,                                                              acetone) 62.9                          ##STR86##                        219-221 (EtOH)                                                                        +73.4 (c = 0.56,                                                                        51.1)                         ##STR87##                        222-223 (EtOH)                                                                        +92.3 (c = 1.23,                                                                        65.1)              __________________________________________________________________________                                                 analysis MS, m/e                                                                              ID]                 __________________________________________________________________________      ##STR88##                                                                                ##STR89##                                                                                       ##STR90##       C.sub.19 H.sub.23 N.sub.3                                                      O.sub.2 S*HCl (C,H,N)                                                                         1                              ##STR91##                        C.sub.13 H.sub.19 N.sub.3                                                      O.sub.2 S*HCl *0.25 H.sub.2 O                                                  C,H,N)         2                              ##STR92##                        C.sub.15 H.sub.23 N.sub.3                                                      O.sub.2 S*HCl (C,H,N)                                                                         3                              ##STR93##                        C.sub.15 H.sub.21 N.sub.3                                                      O.sub.2 S*HCl (C,H,N)                                                                         4                              ##STR94##       ...HN(CH.sub.2 H.sub.5 NH.sub.2                                                                 C.sub.21 H.sub.29 N.sub.3                                                      O.sub.2 S*HCl (C,H,N)                                                                         5                                              ...HN(CH.sub.2).sub.3 NH.sub.2                                                                  C.sub.18 H.sub.23 N.sub.3                                                      O.sub.3 S*HCl  6                                                               (C,H,N)                             ##STR95##                                                                                ##STR96##                                                                                       ##STR97##       C.sub.27 H.sub.24 N.sub.2                                                      O.sub.3 S (C,H,N)                                                                       456                                                                                  739)                           ##STR98##                        C.sub.21 H.sub.20 N.sub.2                                                      O.sub.3 S (C,H,N)                                                                       380                                                                                  829)                           ##STR99##                        C.sub.23 H.sub.24 N.sub.2                                                      O.sub.3 S (C,H,N)                                                                       408                                                                                  928)                           ##STR100##                       C.sub.23 H.sub.22 N.sub.2                                                      O.sub.3 S (C,H,N)                                                                       406                                                                                  10 )                           ##STR101##                       C.sub.29 H.sub.25 N.sub.3                                                      O.sub.3 S (C,H,N)                                                                       495                                                                                  11 )                           ##STR102##                       C.sub.27 H.sub.24 N.sub.2                                                      O.sub.4 S *0.25                                                                         472                                                                                  12 )H,N)            __________________________________________________________________________

                                      TABLE 5                                      __________________________________________________________________________                                                mp, [°C.]                                                                               yield                                                          (cryst. from)                                                                         [α].sub.D.sup.20,                                                        [°]                                                                              [%]                 __________________________________________________________________________      ##STR103##                                                                                 ##STR104##                                                                                   ##STR105##      227-229 (MeOH, Et.sub.2                                                               +44.0 (c = 1.65,                                                               H.sub.2 O)                                                                              51.0                             ##STR106##                    218-219 (EtOH, Et.sub.2                                                               -15.8 (c = 1.16,                                                               H.sub.2 O)                                                                              51.0                             ##STR107##                    194-195 (MeOH, Et.sub.2                                                               +19.5 (c = 1.24,                                                               H.sub.2 O)                                                                              60.4                             ##STR108##                    278-280 (EtOH)                                                                        -127.6 (c = 1.36,                                                              H.sub.2 O)                                                                              87.6                 ##STR109##                                                                                 ##STR110##                                                                                   ##STR111##      179-180 (EtOH)                                                                        +27.0 (c = 1.42,                                                               acetone) 68.4                             ##STR112##                    220-222 (EtOH)                                                                        -63.7 (c = 0.765,                                                              acetone) 67.6                             ##STR113##                    243-244 (EtOH)                                                                        -1.9 (c = 1.035,                                                               acetone) 51.5                             ##STR114##                    219-220 (EtOH)                                                                        -182.7 (c = 1.55,                                                              acetone) 52.1                __________________________________________________________________________                                                analysis  Ms, m/e                                                                               ID]                __________________________________________________________________________      ##STR115##                                                                                 ##STR116##                                                                                   ##STR117##      C.sub.19 H.sub.22 FN.sub.3                                                     O.sub.3 S*HCl (C,H,N)                                                                           13                              ##STR118##                    C.sub.13 H.sub.18 FN.sub.3                                                     O.sub.3 S*HCl (C,H,N)                                                                           14                              ##STR119##                    C.sub.15 H.sub.22 FN.sub.3                                                     O.sub.3 S*HCl *0.5 MeOH                                                        (C,H,N)          15                              ##STR120##                    C.sub.15 H.sub.20 FN.sub.3                                                     O.sub.3 S*HCl (C,H,N)                                                                           16                  ##STR121##                                                                                 ##STR122##                                                                                   ##STR123##      C.sub.27 H.sub.23 FN.sub.2                                                     O.sub.3 S (C,H,N)                                                                        474                                                                                   177)                            ##STR124##                    C.sub.21 H.sub.19 FN.sub.2                                                     O.sub.3 S (C,H,N)                                                                        398                                                                                   184)                            ##STR125##                    C.sub.23 H.sub.23 FN.sub.2                                                     O.sub.3 S (C,H,N)                                                                        426                                                                                   191)                            ##STR126##                    C.sub.23 H.sub.21 FN.sub.2                                                     O.sub.3 S (C,H,N)                                                                        424                                                                                   202)               __________________________________________________________________________

                                      TABLE 6                                      __________________________________________________________________________                                               mp, [°C.] yield                                                         (cryst. from)                                                                          [α].sub.D.sup.20,                                                        [°]                                                                              [%]                 __________________________________________________________________________      ##STR127##                                                                                ##STR128##                                                                                   ##STR129##      229-230 dec (t-amylalcohol)                                                            -84.1 (c = 0.31,                                                               H.sub.2 O)                                                                              25.8                            ##STR130##                    164-166 (EtOH,Et.sub.2 O)                                                              +76.3 (c = 0.46,                                                               H.sub.2 O)                                                                              13.1                            ##STR131##                    235-239 (EtOH,Et.sub.2 O)                                                              -48.4 (c= 0.75, H.sub.2                                                        O)       21.1                            ##STR132##                    285-287 (H.sub.2 O,acetone)                                                            -67.2 (c = 1.07,                                                                        17.4)                           ##STR133##   ...HN(CH.sub.2).sub.5 NH.sub.3                                                                  228-230 dec (t-amylalcohol,                                                    Et.sub.2 O)                                                                            -29.0 (c = 0.21,H.sub.2                                                        O)        9.2                 ##STR134##                                                                                ##STR135##                                                                                   ##STR136##      190-192 (EtOAc)                                                                        +44.5 (c = 0.89,                                                                        51.0)                           ##STR137##                    186-187 (EtOAc)                                                                         -9.7 (c = 0.775,                                                              acetone) 43.4                            ##STR138##                    218-219 (acetone,                                                                      +47.9 (c = 0.94,                                                               acetone) 64.5                            ##STR139##                    180-181 (EtOH)                                                                         -104.0 (c = 0.64,                                                              acetone) 54.4                                                          192-193 --       77.3                                                          (EtOH)                                                         ##STR140##      135-136 (EtOH) Lit[10]: 138                                                    (EtOH,H.sub.2 O)                                                                       --       77.6                __________________________________________________________________________                                                          MS, m/e                                                             analysis   [%]   ID                  __________________________________________________________________________      ##STR141##                                                                                ##STR142##                                                                                   ##STR143##      C.sub.23 H.sub.24 ClN.sub.3                                                    O.sub.3 S*HCl *0.5                                                             t-amylalcohol (C,H,N)                                                                           21                              ##STR144##                    C.sub.19 H.sub.24 ClN.sub.3                                                    O.sub.3 S *0.5 EtOH*0.5 H.sub.2                                                O (C,H,N)        22                              ##STR145##                    C.sub.19 H.sub.22 ClN.sub.3                                                    O.sub.3 S*HCl *0.25 Et.sub.2 O                                                 (C,H,N)          23                              ##STR146##                    C.sub.17 H.sub.20 ClN.sub.3                                                    O.sub.3 S *0.25 acetone *0.25                                                  H.sub.2 O (C,H,N)                                                                               24                              ##STR147##   ...HN(CH.sub.2).sub.6 NH.sub.3                                                                  C.sub.25 H.sub.30 ClN.sub.3                                                    O.sub.3 S*HCl *0.5                                                             t-amylalcohol (C,H,N)                                                                           25                   ##STR148##                                                                                ##STR149##                    C.sub.31 H.sub.25 ClN.sub.2                                                    O.sub.3 S (C,H,N)                                                                         540                                                                                  265)                            ##STR150##                    C.sub.25 H.sub.21 ClN.sub.2                                                    O.sub.3 S (C,H,N)                                                                         464                                                                                  270)                            ##STR151##                    C.sub.27 H.sub.25 ClN.sub.2                                                    O.sub.3 S (C,H,N)                                                                         492                                                                                  288)                            ##STR152##                    C.sub.27 H.sub.23 ClN.sub.2                                                    O.sub.3 S (C,H,N)                                                                         490                                                                                  294)                                                          C.sub.22 H.sub.16 ClNO.sub.2                                                              393                                                                                  300)                                                          (C,H,N)                                                        ##STR153##      C.sub.16 H.sub.12 ClNO.sub.2 S                                                 (C,H,N)    317                                                                                  43 Lit[10]          __________________________________________________________________________

                                      TABLE 7                                      __________________________________________________________________________                                               mp, [°C.] yield                                                         (cryst. from)                                                                          [α].sub.D.sup.20,                                                        [°]                                                                              [%]                 __________________________________________________________________________      ##STR154##                                                                                ##STR155##                                                                                   ##STR156##      238-240 dec (EtOH,t-amyl-                                                      alcohol)                                                                               -58.2 (c = 0.3, H.sub.2                                                        O)       21.4                            ##STR157##                    267-269 dec (amorphous)                                                                +66.4 (c = 0.42,                                                                        13.4)                           ##STR158##                    235-237 dec (EtOH,Et.sub.2 O,                                                  t-amylalcohol)                                                                         -21.3 (c = 0.23,                                                               H.sub.2 O)                                                                              16.9                            ##STR159##                    240-242 dec (MeOH,Et.sub.2                                                             +36.4 (c = 1,43,                                                               H.sub.2 O)                                                                              11.9                            ##STR160##   ...HN(CH.sub.2).sub.6 NH.sub.2                                                                  253-255 dec (t-amylalcohol)                                                            -112.7 (c = 0.73,                                                              H.sub.2 O)                                                                              33.5                                          ##STR161##      115-116 (acetone)                                                                      +21.8 (c = 1.13,                                                               acetone) 24.1                 ##STR162##                                                                                ##STR163##                                                                                   ##STR164##      224-225 (acetone,                                                                      +95.4 (c = 0.87,                                                               acetone) 25.7                            ##STR165##                    170-172 (EtOH)                                                                         -113.5 (c = 0.965,                                                             acetone) 59.4                            ##STR166##                    185-186 (acetone,                                                                      +22.8 (c = 0.63,                                                               acetone) 38.4                            ##STR167##                    178-179 (EtOH)                                                                         +113.2 (c = 1.095,                                                             aceotne) 58.8                                                          174-175 --       32.8                                                          (acetone, pentane)                                             ##STR168##      154-155 dec (acetone, Et.sub.2                                                 O)      --       32.1                __________________________________________________________________________                                                          MS, m/e                                                             analysis   [%]   ID                  __________________________________________________________________________      ##STR169##                                                                                ##STR170##                                                                                   ##STR171##      C.sub.22 H.sub.24 N.sub.4                                                      O.sub.3 S*2HCl *H.sub.2 O                                                      (C,H,N)          31                              ##STR172##                    C.sub.18 H.sub.24 N.sub.4                                                      O.sub.3 S*2HCl *0.5                                                            EtOH*H.sub.2 O (C,H,N)                                                                          32                              ##STR173##                    C.sub.18 H.sub.22 N.sub.4                                                      O.sub.3 S*2HCl   33                              ##STR174##                    C.sub.16 H.sub.20 N.sub.4                                                      O.sub.3 S*2HCl *0.5                                                            MeOH*H.sub.2 O (C,H,N)                                                                          34                              ##STR175##   ...HN(CH.sub.2).sub.6 NH.sub.2                                                                  C.sub.24 H.sub.30 N.sub.4                                                      O.sub.3 S*2HCl *0.25                                                           t-amylalcohol (C,H,N)                                                                           35                                            ##STR176##      C.sub.30 H.sub.25 N.sub.3                                                      O.sub.3 S *acetone (C,H,N)                                                                507                                                                                  361)                 ##STR177##                                                                                ##STR178##                                                                                   ##STR179##      C.sub.26 H.sub.25 N.sub.3                                                      O.sub.3 S (C,H,N)                                                                         459                                                                                  377)                            ##STR180##                    C.sub.26 H.sub.23 N.sub.3                                                      O.sub.3 S (C,H,N)                                                                         457                                                                                  385)                            ##STR181##                    C.sub.24 H.sub.21 N.sub.3                                                      O.sub.3 S (C,H,N)                                                                         431                                                                                  395)                            ##STR182##                    C.sub.26 H.sub.23 N.sub.3                                                      O.sub.3 S (C,H,N)                                                                         457                                                                                  402)                                                          C.sub.21 H.sub.16 N.sub.2                                                      O.sub.2 S  360                                                                                  413)                                                          (C,H,N)                                                        ##STR183##      C.sub.15 H.sub.12 N.sub.2                                                      O.sub.2 S (C,H,N)                                                                         284                                                                                  429)                __________________________________________________________________________

                                      TABLE 8                                      __________________________________________________________________________     .sup.1 H-NMR (300 MHz, D.sub.2 O)                                                                                                      H--C(1")                                                 H--C(5')              H--C(2")                 H--C(2)                                                                             H--C(3)                    H--C(6')         H--C(4')/                                                                           H--C(3")               ID                                                                               H--C(6)                                                                             H--C(5)                                                                             H--C(4)                                                                             H--C(1')                                                                             H--C(2')                                                                             H--C(3')                                                                            H--C(7')                                                                            H.sub.3 C--C(1')                                                                     H.sub.3 C--C(2')                                                                     H--C(8')                                                                            H--C(4")               __________________________________________________________________________     1 7.82 7.62 7.73 4.52  3.06, 2.91 7.36             7.20 1.73 (1)                 m    m    m    dxd   2xdx       m                m    2.67 (1)                                (9.84, 6.10)                                                                         (12.97, 6.06)                    2.85 (1)                                      (12.96, 9.88)                    2.93-3.01 (2)                                                                  3.24 (1)                                                                       3.35 (1)                                                                       3.68 (1)                                                                       all m                  2 7.88 7.67 7.76 4.43                  1.28             3.01 (1)                 m    m    m    q                     d                3.16 (1)                                (6.96)                (6.96)           3.23 (1)                                                                       3.31 (1)                                                                       3.56 (2)                                                                       3.80 (2)                                                                       all m                  3 7.87 7.66 7.76 4.05  1.93                  0.89, 0.93 2.89 (1)                 br d m    br 1 d     "sextex"              2d         3.01 (1)                                (6.78)                      (6.72, 6.76)                                                                              3.14-3.27 (2)                                                                  3.43-3.60 (2)                                                                  3.68 (1)                                                                       3.80 (1)                                                                       all m                  4 7.90 7.69 7.79 4.69  1.71 (1)                    3.30-3.42 (5)                 m    m    m    m     1.90 (2)                    3.55 (1)                                           2.15 (1)                    3.81 (1)                                                                       3.89-3.07 (3)                                                                  all m                       __________________________________________________________________________

                                      TABLE 9                                      __________________________________________________________________________     .sup.1 H-NMR (300 MHz, D.sub.2 O)                                                                                   H--C(1")                                                                       H--C(2")                                                                       H--C(3")                                                             H--C(5')  H--C(4")                                    H--C(2)                                                                             H--C(3)        H--C(4')/                                                                           H--C(6')  H--C(5")                                  ID                                                                               H--C(6)                                                                             H--C(5)                                                                             H--C(4)                                                                             H--C(1')                                                                            H--C(8')                                                                            H--C(7')                                                                            H--C(2')                                                                            H--C(6")                                  __________________________________________________________________________     5 7.72 7.54 7.67 3.94 7.11 7.26 1.05 (2)                                         2br d                                                                               br t br t t    m    m    1.18-1.28 (4)                                                   (7.75)         1.60 (2)                                                                       2.74 (1)                                                                       2.84-2.99 (5)                                                                  all m                                          6 7.72 7.55 7.68 3.95 7.11 7.27 2.92 (2)                                                                            1.60 br q (2)                               2br d                                                                               br t br t t    m    m    d    2.60 (2)                                                   (7.83)         (7.98)                                                                              2.91 (1)                                                                       3.02 (1)                                                                       m                                         __________________________________________________________________________

                                      TABLE 10                                     __________________________________________________________________________     .sup.1 H-NMR (300 MHz, acetone-d.sub.6 (7) or DMSO-d.sub.6                     __________________________________________________________________________     (12))                                                                            H--C(3)   H--C(2")   H--C(9")                                                                             H--C(3")                                                                            H--C(2)                                                                             H--C(8")                                ID                                                                               H--C(5)                                                                             H--C(4)                                                                             H--C(6")                                                                            H--C(10")                                                                            H--C(11")                                                                            H--C(5")                                                                            H--C(6)                                                                             H--C(12")                               __________________________________________________________________________      7                                                                               7.48-8.58 (5)  7.33  7.44 (4)   7.77 7.63                                      m              br t  m          br d br d                                    12                                                                               7.35-7.53 (8)              7.61 7.68 (4)                                       m                          d    m                                                                         (8.55)                                            __________________________________________________________________________                             H--C(5')                                                                  H--C(4')/                                                                           H--C(6')                                               ID  H--C(1')                                                                            H--C(2')  H--C(8')                                                                            H--C(7') NHSO.sub.2"                                                                         NHCO.sub."                               __________________________________________________________________________      7  4.29 2.94, 3.12                                                                               7.20 (5)      6.97 9.29                                         br t 2xdx      m             br s s                                                 (13.70, 7.85)                                                                  (13.70, 6.58)                                                         12  4.07 2.71, 2.90                                                                               7.02 6.66 (2)      10.36                                        m    2dxd      br d d             brs                                               (13.55, 8.63)  (8.29)                                                          (13.61, 6.14)                                                         __________________________________________________________________________

                                      TABLE 11                                     __________________________________________________________________________     .sup.1 H-NMR (300 MHz, acetone-d.sub.6)                                        __________________________________________________________________________        H--C(2)                                                                             H--C(3)   H--C(8")                                                                             H--C(3")                                                                            H--C(2")                                                                            H--C(9")                                     ID H--C(6)                                                                             H--C(5)                                                                             H--C(4)                                                                             H--C(12")                                                                            H--C(5")                                                                            H--C(6")                                                                            H--C(11")                                                                            H--C(10")                                                                            H--C(1')                         __________________________________________________________________________     8  7.93 7.53-7.65 (9)             7.44  7.33  4.08                                2br d                                                                               m                         br t  br t  q                                                                              (7.06)                           9  7.88           7.41-7.64 (11)        7.33  3.81                                m              m                     br t  m                                10 7.97 7.82 7.77 7.70  7.66 (4)  7.46  7.34  4.27                                2br d                                                                               2br d                                                                               m    2d    m         2br t br t  m                                __________________________________________________________________________                           H--C(5')                                                               H--C(4')/                                                                              H--C(6')                                                 ID H--C(2')                                                                            H--C(3')                                                                             H--C(8')                                                                               H--C(7')                                                                             H.sub.3 C--C(1')                                                                     H.sub.3 C--C(2')                                                                      NHSO.sub.2"                                                                         NHCO.sub."                       __________________________________________________________________________     8                           1.33         6.98 9.31                                                         d            br s s                                                            (7.06)                                             9  2.08                           0.96, 0.97                                                                            6.71 9.33                                m                              2d     d    br s                                                               (6.75, 6.79)                                                                          (9.08)                                10 1.66, 1.81, 1.93, 2.11 (4)                                                                3.34, 3.64                      9.41                                m          2dxdxd                          s                                              (9.98, 7.92, 6.95                                                              (10.0, 6.94, 4.26                                                __________________________________________________________________________

                                      TABLE 12                                     __________________________________________________________________________     .sup.1 H-NMR (300 MHz, DMSO-d.sub.6)                                           __________________________________________________________________________       H--C(2)                                                                             H--C(8")                                                                             H--C(3)             H--C(9")                                      ID                                                                               H--C(6)                                                                             H--C(12")                                                                            H--C(5)                                                                             H--C(4'")                                                                           H--C(7'")                                                                           H--C(4)                                                                             H--C(11")                                                                            H--C(10")                               __________________________________________________________________________     11                                                                               7.68, 7.72 (4)                                                                            7.49 (4)       7.38 (4)                                             2br d      m              br t                                               __________________________________________________________________________                                   H--C(3")                                                                             H--C(2")                                   ID                                                                               H--C(1')                                                                            H--C(2')                                                                             H--C(2'")                                                                           H--C(5'")                                                                             H--C(6'")                                                                           H--C(5")                                                                             H--C(6")                                                                            NH.sub.'"                             __________________________________________________________________________     11                                                                               4.26 3.12, 3.29                                                                           7.16 6.98   7.10 7.58 (4)   10.97                                   br t 2dxd  br s dxd    t    m          br s                                         (14.45, 7.02)                                                                             (7.55, 7.19)                                                                          (7.48)                                                       (14.45, 6.8)                                                            __________________________________________________________________________

                                      TABLE 13                                     __________________________________________________________________________     .sup.1 H-NMR (300 MHz, D.sub.2 O)                                                                                      H--C(1")                                                                       H--C(2")    H--C(5')                     H--C(2)                                                                             H--C(3)                          H--C(3")                                                                              H--C(4')/                                                                           H--C(6')                   ID                                                                               H--C(6)                                                                             H--C(5)                                                                             H--C(1')                                                                             H.sub.3 C--C(1')                                                                     H.sub.3 C--C(2')                                                                     H--C(3')                                                                            H--C(2')                                                                            H--C(4")                                                                              H--C(8')                                                                            H--C(7')                   __________________________________________________________________________     13                                                                               7.82 7.20 4.53                   1.84 (1)    7.33 (5)                          m    m    dxd                    2.65 (1)    m                                           (9.38, 6.47)           2.89-3.12 (5)                                                                  3.37 (1)                                                                       3.47 br d (1)                                                                  3.78 br d (1)                                                                  all m                                       14                                                                               7.92 7.38 4.45  1.28                  3.12 (1)                                 2 br d                                                                              m    q     d                     3.22-3.37 (3)                                      (6.95)                                                                               (6.95)                3.63-3.68 (2)                                                                  3.80-3.90(2)                                                                   all m                                  15                                                                               7.91, 7.92                                                                          7.38 4.07        0.87, 0.93 1.94 3.03 (1)                                 2br d                                                                               br t d           2d         "sextet"                                                                            3.12-3.31 (3)                                      (6.75)      (6.70, 6.75)    3.50 (1)                                                                       3.63-3.78 (2)                                                                  3.88 (1)                                                                       all m                                  16                                                                               7.94 7.40 4.71              1.73 (1)  3.33--3.44 (5)                           2br d                                                                               br t m                 1.92 (2)  3.54 (1)                                                             2.19 (1)  3.81-3.87 (1)                                                        m         3.91-4.07 (3)                                                                  all m                                  __________________________________________________________________________

                                      TABLE 14                                     __________________________________________________________________________     .sup.1 H-NMR (300 MHz, acetone-d.sub.6)                                        __________________________________________________________________________                                           H--C(5')                                    H--C(2)                                                                             H--C(3)               H--C(4')/                                                                              H--C(6')                                 1D H--C(6)                                                                             H--C(5)                                                                             H--C(1')                                                                             H--C(2')                                                                             H--C(3')                                                                            H--C(8')                                                                               H--C(7')                                                                            H.sub.3 C--C(1')                    __________________________________________________________________________     17 7.79 7.11 4.26  2.96, 3.41 7.19 (5)                                            2br d                                                                               m    dxd   2dxd       m                                                             (8.45, 6.25)                                                                         (13.73, 8.45)                                                                  (13.73, 6.19)                                               18 7.97 7.30 4.10                          1.35                                   2br d                                                                               br d q                             d                                                (7.06)                        (7.06)                              19 7.95, 7.93                                                                          7.23, 7.20                                                                          3.80  2.08                                                           2br d                                                                               2br d                                                                               m     m                                                              (9.06)                                                                         (9.04)                                                                      20 8.05 7.81 4.28  1.71, 1.84-2.00, 2.13 (4)                                                                 3.63, 3.35                                          2br d                                                                               br d m     m          2dxdxd                                                                         (9.99, 6.94, 4.64                                                              (9.87, 7.91, 6.76                                __________________________________________________________________________             H--C(8")                                                                              H--C(3")                                                                            H--C(2")                                                                             H--C(9")                                             1D                                                                               H.sub.3 C--C(2')                                                                     H--C(12")                                                                             H--C(5")                                                                            H--C(6")                                                                             H--C(11")                                                                            H--C(10")                                                                             NHSO.sub.2"                                                                         NHCO.sub."                         __________________________________________________________________________     17      7.61   7.55 (4)   7.43  7.32        9.29                                       br d   br s       br t  br t        s                                  18      7.58-7.65 (6)     7.45  7.33   7.06 9.34                                       m                 br t  br t   br s s                                  19                                                                               0.97 (d)                                                                             7.63   7.56 (4)   7.45  7.33   6.83 9.42                                 d     m      m          2br t br t   m    br s                                 (6.84)                                                                       20      7.65 (4)    7.45 (4)    7.34        9.41                                       m           m           br t        s                                  __________________________________________________________________________

                                      TABLE 15                                     __________________________________________________________________________     .sup.1 H-NMR (300 MHz, DMSO-d.sub.6 (21), D.sub.2 O)                           __________________________________________________________________________     ID H--C(2)                                                                             H--C(3)                                                                              H--C(7)                                                                              H--C(8)                                                                              H--C(4)                                                                              NHSO.sub.2"                                                                         H--C(6)                                                                              H--C(1')                            __________________________________________________________________________     21 8.63 8.04  7.73, 7.58*                                                                          8.46, 8.19*                                                                          7.69       8.12, 7.86*                                                                          4.37                                   d    dxd   2dxd  2d    m          2d    t                                      (8.83)                                                                              (9.19, 7.72)                                                                         (8.09, 7.73)                                                                         (8.09, 8.46)     (7.36, 7.35)                                                                         (7.36)                              22 8.56 7.65  7.80  8.25  7.72  7.68 8.08  3.91                                   d    dxd   br dxd                                                                               d     d     br s d     d                                      (8.46)                                                                              (8.09, 7.72)                                                                         (8.09, 7.36)                                                                         (7.36)                                                                               (7.35)     (7.72)                                                                               (7.35)                              23 8.63 7.65-7.80   8.26             8.09  5.00                                   d    m           m                d     m                                      (8.49)                            (8.08)                                    24 8.58 7.66  7.72  8.26  7.80  8.24 8.09  4.37                                   br d dxd   dxd   br d  dxd   s    br d  q                                      (8.24)                                                                              (7.88, 7.77)                                                                         (7.50)                                                                               (7.45)                                                                               (7.74, 1.42)                                                                              (7.98)                                                                               (6.96)                              __________________________________________________________________________                    H--C(1")                                                                       H--C(2")     H--C(5')                                                          H--C(3")                                                                               H--C(4')/                                                                           H--C(6')                                           ID H--C(3')                                                                              H--C(2')                                                                            H--C(4")                                                                               H--C(8')                                                                            H--C(7')                                                                              H.sub.3 C--C(1')                                                                     H.sub.3 --C(2')                       __________________________________________________________________________     21        2.00 (1)     7.13 (2)                                                                            7.06                                                         2.36 (2)     m    m                                                            2.66-2.83 (3)                                                                  3.03 (2)                                                                       3.19-3.33 (2)                                                                  all m                                                                22        1.86 2.63 (1)                  0.82, 0.85                                      "sextet"                                                                            2.81 (1)                  2d                                                   3.05 (3)                                                                       3.25-3.42 (2)                                                                  3.64 (1)                                                                       all m                                                           23 1.85-2.05 (3)                                                                              3.13 (1)                                                           2.27 (1)    3.26 (3)                                                           m           3.54-3.91 (6)                                                                  all m                                                           24             2.73 (1)            1.21                                                       2.89 (1)            d                                                          3.05-3.27 (4)       (6.98)                                                     3.51-3.62 (2)                                                                  all m                                                           __________________________________________________________________________      *doubling of the signals                                                 

                                      TABLE 16                                     __________________________________________________________________________     .sup.1 H-NMR (300 MHz, D.sub.2 O)                                              __________________________________________________________________________     ID                                                                               H--C(1)                                                                             H--C(2)                                                                             H--C(7)                                                                              H--C(3)                                                                             H--C(4)                                                                             H--C(6)                                                                             H--C(8)                                       __________________________________________________________________________     25     8.63 7.65-7.80  7.90 8.09 8.25                                                 d    m          m    d    d                                                    (8.38)               (7.82)                                                                              (7.39)                                        35                                                                               9.66      8.02  8.52      8.61                                                 s         dxd   m         2d                                                             (8.09, 7.72)    (7.72)                                             __________________________________________________________________________             H--C(4')                                                                       H--C(5')           H--C(2")                                                    H--C(6')           H--C(3")                                                    H--C(7')    H--C(1")                                                                              H--C(4")                                            ID                                                                               H--C(1')                                                                             H--C(8')                                                                            H--C(2')                                                                              H--C(6")                                                                              H--C(5")                                                                              NH.sub."                                     __________________________________________________________________________     25                                                                               3.88  6.87 (5)                                                                            3.02-3.13 (6) 1.45 (6)                                              "t"   m    m             1.77 (2)                                              (7.38)                   m                                                   35                                                                               3.88  6.68 (5)                                                                            2.96, 2.62                                                                            3.16, 3.02 (4)                                                                        1.32-1.55 (6)                                                                         8.36                                           dxd   m    2dxd   m      1.69 (2)                                                                              br t                                           (11.40, 4.41)                                                                             (14.52, 4.23) m                                                                (14.13, 11.21)                                                    __________________________________________________________________________

                                      TABLE 17                                     __________________________________________________________________________     .sup.1 H-NMR (300 MHz, acetone-d.sub.6, CDCl.sub.3 (43))                       __________________________________________________________________________                                                          H--C(4')/                 ID                                                                               H--C(2)                                                                             H--C(3)                                                                              H--C(4)                                                                              H--C(6)                                                                              H--C(8)                                                                             H--C(7)                                                                              H--C(1')                                                                             H--C(2')                                                                             H--C(3')                                                                            H--C(8')                  __________________________________________________________________________     26                                                                               8.67 7.62  7.75  8.21  8.37 7.60  4.24  2.85, 3.07 7.01                        br d dxd   dxd   dxd   br d dxd   dxd   2dxd       m                           (8.72)                                                                              (8.69, 7.52)                                                                         (7.52, 0.94)                                                                         (7.36, 1.18)                                                                         (8.55)                                                                              (8.57, 7.35)                                                                         (9.02, 5.73)                                                                         (13.80, 9.02)                                                                  (13.80, 5.73)                        27                                                                               8.84 7.70  7.80  8.38  8.46 7.73  4.10                                         br d dxd   br d  dxd   br d dxd   q                                            (8.67)                                                                              (8.64, 7.57)                                                                         (7.51)                                                                               (7.35, 1.14)                                                                         (8.56)                                                                              (8.53, 7.39)                                                                         (7.06)                                     28                                                                               8.85 7.68  7.76  8.36       7.67  3.72  2.00                                   d    dxd   dxd   2br d      dxd   d     m                                      (8.60)                                                                              (8.44, 7.54)                                                                         (7.48, 1.06)     (8.53, 7.26)                                                                         (7.32)                                     29                                                                               8.97 7.71  7.82  8.44  8.58 7.82  4.50  1.84, 2.06, 2.14                                                                          3.63                        br d dxd   dxd   dxd   br d dxd   m     m          m                           (8.72)                                                                              (8.72, 7.56)                                                                         (7.50, 0.96)                                                                         (7.40, 1.12)                                                                         (8.55)                                                                              (8.54, 7.43)                                     30                                                                               8.86 7.71  7.82  8.42  8.56 7.78                                               d    dxd   d     br d  d    dxde                                               (8.70)                                                                              (8.52, 7.71)                                                                         (7.40)                                                                               (7.35)                                                                               (8.57)                                                                              (8.36, 7.35)                                     43                                                                               8.67 7.56  7.69  8.27  8.54 7.57                                               br d dxd   dxd   dxd   br d dxd                                                (8.82)                                                                              (8.82, 7.36)                                                                         (7.35, 1.10)                                                                         (7.35, 1.10)                                                                         (8.46)                                                                              (8.45, 7.35)                                     __________________________________________________________________________       H--C(6')         H--C(3")                                                                            H--C(2")                                                                            H--C(9")                                                                             H--C(8")                                    ID                                                                               H--C(7')                                                                            H.sub.3 C--C(1')                                                                     H.sub.3 C--C(2')                                                                     H--C(5")                                                                            H--C(6")                                                                            H--C(11")                                                                            H--C(12")                                                                            H--C(10")                                                                             NHCO.sub."                                                                         NHSO.sub.2"                __________________________________________________________________________     26                                                                               6.92             7.44-7.54       7.64  7.34   9.22                             m                m               br d  br t   s                              27     1.28        7.37 7.51 7.44  7.62  7.33   9.09                                  d           m    br d br t  2d    br t   s                                     (7.06)                                                                  28           0.84, 0.92                                                                           7.24 7.46       7.61  7.33   9.07                                                                               7.15                                    2d    m    m          2d    br t   br s                                                                               br s                                    (6.72)                                                            29                 7.56      7.45  7.64  7.33   9.13                                              m         br t  2d    br t   s                              30                 7.47 7.22 7.39  7.52  7.29       9.61                                          br d br d br t  br d  br t       s                                             (8.60)                                                                              (8.61)     (7.27)                                      43                           7.04-7.14   6.93       6.93                                                    m           m          m                                                                   [H--C(4")]                            __________________________________________________________________________

                                      TABLE 18                                     __________________________________________________________________________     .sup.1 H-NMR (300 MHz, D.sub.2 O)                                              __________________________________________________________________________     ID                                                                               H--C(1)                                                                              H--C(3)                                                                             H--C(4)                                                                               H--C(8)                                                                             H--C(6)                                                                               H--C(7)                                                                             H--C(1')                                  __________________________________________________________________________     31                                                                               9.72  8.59        8.65        8.05 4.43                                        s     s           2br d       "t"  dxd                                                                            (10.30, 5.89)                             32                                                                               9.85  9.06 8.78   8.77        8.16 4.11                                        s     d    d      d           "t"  d                                                 (6.99)                                                                              (6.99) (7.73)      (8.09)                                                                              (6.98)                                                        8.82                                                                           dxd                                                                            (8.45, 1.10)                                               33                                                                               9.83  9.10 8.75        8.81   8.16 5.01                                        s     d    m           d      "t"  m                                                 (6.91)           (7.47) (7.94)                                         34                                                                               9.71  8.85 8.71   8.65 8.69   8.05 4.51                                        s     d    d      d    d      "t"  q                                                 (6.77)                                                                              (6.77) (8.31)                                                                              (7.50) (7.90)                                                                              (7.03)                                    __________________________________________________________________________                             H--C(1")                                                             H--C(5')  H--C(2")                                                             H--C(6')                                                                            H--C(4')/                                                                           H--C(3")                                               ID                                                                               H--C(2')                                                                              H--C(3')                                                                            H--C(7')                                                                            H--C(8')                                                                            H--C(4")                                                                              H.sub.3 C--C(1')                                                                     H.sub.3 C--C(2')                          __________________________________________________________________________     31                                                                               2.74, 2.90  6.82 (5)  2.89 (1)                                                 2dxd        m         3.13-3.33 (3)                                            (13.78, 10.48)        3.62-3.85 (4)                                            (13.79, 5.70)         all m                                                  32                                                                               1.90                  3.03 (1)     0.72, 0.81                                  "sextet"              3.17 (1)     2d                                                                3.23 (2)     (6.62)                                                            3.36 (1)                                                                       3.57 (1)                                                                       3.76 (1)                                                                       3.89 (1)                                                                       all m                                                  33                                                                               1.98 (3)         3.36 (4)                                                      2.36 (1)         3.55 (2)                                                      m                3.73-3.90 (2)                                                                  3.91-4.05 (2)                                                                  all m                                                       34                      3.02 (1)                                                                              1.21                                                                    3.30 (5)                                                                              d                                                                       3.78 (2)                                                                              (7.03)                                                                  all m                                                  __________________________________________________________________________

                                      TABLE 19                                     __________________________________________________________________________     .sup.1 H-NMR (300 MHz, acetone-d.sub.6)                                        __________________________________________________________________________                                                        H--C(4')/                   ID                                                                               H--C(1)                                                                             H--C(3)                                                                             H--C(4)                                                                             H--C(6)                                                                              H--C(8)                                                                             H--C(7)                                                                              H--C(1')                                                                             H--C(2')                                                                             H--C(3')                                                                            H--C(8')                    __________________________________________________________________________     36                                                                               9.27 8.57 8.37 8.13, 8.17 in the region                                                                        4.08  2.75, 2.90 7.02                          s    d    d    2d         7.53-7.64                                                                            dxd   2dxd       m                                  (6.07)                                                                              (6.10)                                                                              (7.37, 8.27)                                                                              m     (9.53, 4.89)                                                                         (13.60, 9.75)                                                                  (13.60, 4.80)                          37                                                                               9.31 8.69 8.61 8.45  8.22 7.69  3.78  2.03                                     br s d    br d dxd   br d dxd   m     m                                             (6.14)                                                                              (6.07)                                                                              (7.36, 1.35)                                                                         (8.26)                                                                              (8.15, 7.45)                                       38                                                                               9.43 8.72 8.69 8.55  8.43 7.85  4.55  1.81, 2.05-2.13,                                                                          3.57, 3.68                    br s br d d    dxd   br d dxd   m     m          m                                       (6.16)                                                                              (7.39, 1.24)                                                                         (8.21)                                                                              (8.15, 7.47)                                       39                                                                               9.39 8.70 8.60 8.47  8.31 7.74  4.14                                           br s br d br d d     d    br t  m                                                             (7.34)                                                                               (8.18)                                                  41                                                                               9.43 8.69 8.58 8.51  8.39 7.79                                                 br s d    d    dxd   d    t                                                         (6.08)                                                                              (6.15)                                                                              (7.39, 1.05)                                                                         (8.22)                                                                              (7.83)                                             42                                                                               9.42 8.67 8.54 8.45  8.39 7.78                                                 d    d    br d dxd   d    br t                                                 (0.66)                                                                              (6.10)                                                                              (6.07)                                                                              (7.39, 1.17)                                                                         (8.22)                                                                              (7.82)                                             __________________________________________________________________________       H--C(5')                                                                       H--C(6')         H--C(3")                                                                            H--C(2")                                                                            H--C(9")                                                                             H--C(8")                                    ID                                                                               H--C(7')                                                                            H.sub.3 C--C(1')                                                                     H.sub.3 C--C(2')                                                                     H--C(5")                                                                            H--C(6")                                                                            H--C(11")                                                                            H--C(12")                                                                            H--C(10")                                                                            NHCO.sub."                                                                         NHSO.sub.2"                 __________________________________________________________________________     36                                                                               6.89             7.38-7.47, 7.53-7.64  7.33  10.23                             m                m                     br t  s                               37           0.86, 0.91                                                                           7.41-7.50 7.27-7.35, 7.61   9.20                                         2d    m         m                 br s                                         (6.72)                                                            38                 7.58-7.66 7.44  7.58-7.66                                                                            7.33  9.42                                               m         br t  m     br t  s                               39     1.30        7.39-7.51 7.43  7.61  7.33  9.23                                                                               7.55                               d           m         m     br d  br t  br s                                                                               br s                               (7.05)                                                                  41                 7.48 7.23 7.39  7.52  7.29      9.66                                           br d br d br t  br d  br t      br s                                           (8.64)                                                                              (8.66)     (7.32)                                      42                 7.15                  7.00      9.51                                           m                     br t      br s                                                                 [H--C(4")]                            __________________________________________________________________________

                  TABLE 20                                                         ______________________________________                                                     IC.sub.50.sup.1)                                                           ID  (μM)                                                            ______________________________________                                                  1  promotion.sup.2)                                                            2  promotion.sup.3)                                                            7  310                                                                        10  520                                                                        11  570                                                                        21  600                                                                        22  310                                                                        25   67                                                                        30  275                                                                        31  promotion.sup.4)                                                           35  263                                                                        37  470                                                                        38  130                                                                        40  435                                                                        41  promotion.sup.5)                                                           43  190                                                                ______________________________________                                          .sup.1) Compounds are only listed if their IC.sub.50 is lower than 600         μM.                                                                         .sup.2) Promotion of the hydrolysis rate at 100 mM: 138% of the value in       absence of an inhibitor.                                                       .sup.3) Promotion of the hydrolysis rate at 100 mM: 125% of the value in       absence of an inhibitor.                                                       .sup.4) Inhibition at 100 μM: 70.1%, at 300 μM 54.0%.                    .sup.5) Inhibition at 10 μM: 31.6%, at 100 μM 28.3%.                

I claim:
 1. Compounds of the general formula ##STR184## wherein Z is phenyl, naphthyl, (5)- or (8)-isoquinolyl, possibly substituted by halogen; except that Z is not phenyl when both A is L-proline and R₂ is phenyl;A is selected from the group consisting of L-phenylalanine, L-alanine, L-proline, L-valine, L-tryptophane and L-tyrosine moieties, where the N atom of the α-amino group which defines A as an amino acid is bound to SO₂ and its carboxyl group to the N atom of formula I, R₁ is hydrogen, and R₂ is phenyl, biphenyl, a C₂ to C₆ -alkylamine; except that R₂ is not phenyl when A is L-valine or L-alanine; or R₁ and R₂ together form the piperazine ring, except that R₁ and R₂ together do not form the piperazine ring when A is L-phenylalanine or L-tyrosine,or its pharmaceutically acceptable non-toxic acid addition salts with inorganic or organic acids.
 2. Compounds of one of the formulas: ##STR185## wherein A is selected from the group consisting of L-phenylalanine, L-alanine, L-proline, L-valine, L-tryptophane and L-tyrosine moieties, where the N atom of the α-amino group which defines A as an amino acid is bound to SO₂ and its carboxyl group to the N atom of formula II, III or IV,R₁ is hydrogen, and R₂ is phenyl, biphenyl, a C₂ to C₆ -alkylamine; except that R₂ is not phenyl when A is L-valine or L-alanine; or R₁ and R₂ together form the piperazine ring, except that R₁ and R₂ together do not form the piperazine ring when A is L-phenylalanine or L-tyrosine, Y is F, Cl, Br, being the same or different, and n is 0, 1 or 2; except that compound (II) cannot have both A as L-proline and R₂ as phenyl;or their pharmaceutically acceptable non-toxic acid addition salts with inorganic or organic acids.
 3. The compounds of claim 1, wherein A is the L-phenylalanine, L-alanine, L-valine or L-proline group.
 4. The compounds of claim 1, wherein A is the L-phenylalanine group.
 5. Compounds of claim 1, wherein R₁ and R₂ together form the piperazine ring.
 6. Compounds of claim 2 of formula III, whereinY is F or Cl in 5-position n is 1 R₁ is hydrogen, and R₂ is biphenyl.
 7. Compounds of claim 2 of formula IV, whereinY is hydrogen n is 0 R₁ is hydrogen, and R₂ is biphenyl.
 8. A method of inhibiting Ca²⁺ -dependent enzymes and proteins consisting of Phospholipase A₂ (PLA₂), for the treatment of inflammation, comprising contacting the (PLA₂) with an effective amount of the compounds of claim
 1. 9. A pharmaceutical composition for inhibiting Ca²⁺ -dependent enzymes and proteins, the composition comprising compounds of the formula: ##STR186## wherein Z is phenyl, naphthyl, (5)- or (8)-isoquinolyl, possibly substituted by halogen; except that Z is not phenyl when both A is L-proline and R₂ is phenyl;A is selected from the group consisting of L-phenylalanine, L-alanine, L-proline, L-valine, L-tryptophane and L-tyrosine moieties, where the N atom of the amino group which defines A as an α-amino add is bound to SO₂ and its carboxyl group to the N atom of formula I R₁ is hydrogen, and R₂ is phenyl biphenyl, a C₂ to C₆ -alkylamine; except that R₂ is not phenyl when A is L-valine or L-alanine; or R₁ and R₂ together form the piperazine ring, except that R₁ and R₂ together do not form the piperazine ring when A is L-phenylalanine or L-tyrosine,or their pharmaceutically acceptable non-toxic acid addition salts selected from the group consisting of the salts of inorganic acids in turn selected from the group consisting of hydrochloric acid, phosphoric acid and sulfuric add; and the salts of organic acids in turn selected from the group consisting of citric acid, tartaric acid and methanesulfonic add.
 10. Compounds of claim 2 wherein A is the L-phenylalanine, L-alanine, L-proline or L-valine group.
 11. Compounds of claim 2 wherein A is the L-phenylalanine group.
 12. Compounds of claim 2 whereinR₁ is hydrogen, R₂ is biphenyl.
 13. Compounds of claim 3 whereinR₁ is hydrogen, R₂ is biphenyl.
 14. Compounds of claim 4 whereinR₁ is hydrogen, R₂ is biphenyl.
 15. Compounds of claim 2, wherein R₁ and R₂ together form the piperazine ring.
 16. Compounds of claim 3, wherein R₁ and R₂ together form the piperazine ring, except that R₁ and R₂ together do not form the piperazine ring when A is L-phenylalanine.
 17. Compounds of claim 15 with formula III, whereinY is F or Cl in 5-position n is 1 R₁ is hydrogen, and R₂ is biphenyl.
 18. Compounds of claim 16 with formula III, whereinY is F or Cl in 5-position n is 1 R₁ is hydrogen, and R₂ is biphenyl.
 19. Compounds of claim 15 with formula IV, whereinY is hydrogen n is 0 R₁ is hydrogen, and R₂ is biphenyl.
 20. Compounds of claim 16 with formula IV, whereinY is hydrogen n is 0 R₁ is hydrogen, and R₂ is biphenyl.
 21. A method of inhibiting Ca²⁺ -dependent enzymes and proteins consisting of Phospholipase A₂ (PLA₂), for the treatment of inflammation, comprising contacting the (PLA₂) with an effective amount of a compound of claim
 2. 22. A method of inhibiting Ca²⁺ -dependent enzymes and proteins consisting of Phospholipase A₂ (PLA₂), for the treatment of inflammation, comprising contacting the (PLA₂) with an effective amount of a compound of claim
 3. 23. A method of inhibiting Ca²⁺ -dependent enzymes and proteins consisting of Phospholipase A₂ (PLA₂), for the treatment of inflammation, comprising contacting the (PLA₂) with an effective amount of a compound of claim
 4. 24. A method of inhibiting Ca²⁺ -dependent enzymes and proteins consisting of Phospholipase A₂ (PLA₂), for the treatment of inflammation, comprising contacting the (PLA₂) an effective amount of a compound of claim
 6. 25. A method of inhibiting Ca²⁺ -dependent enzymes and proteins consisting of Phospholipase A₂ (PLA₂), for the treatment of inflammation, comprising contacting the (PLA₂) with an effective amount of a compound of claim
 5. 26. A method of inhibiting Ca²⁺ -dependent enzymes and proteins consisting of Phospholipase A₂ (PLA₂), for the treatment of inflammation, comprising contacting the (PLA₂) with an effective amount of a compound of claim
 6. 27. A method of inhibiting Ca²⁺ -dependent enzymes and proteins consisting of Phospholipase A₂ (PLA₂), for the treatment of inflammation, comprising contacting the (PLA₂) with an effective amount of a compound of claim
 7. 28. The method of inhibiting Ca²⁺ -dependent enzymes and proteins consisting of Phospholipase A₂ (PLA₂), for the treatment of inflammation, comprising contacting the (PLA₂) an effective amount of a composition of claim
 13. 29. Compounds of the general formula ##STR187## wherein Z is phenyl, naphthyl, (5)- or (8)-isoquinolyl, possibly substituted by halogen;A is selected from the group consisting of L-phenylalanine, L-alanine, L-proline, L-valine, L-tryptophane and L-tyrosine moieties, where the N atom of the α-amino group which defines A as an amino acid is bound to SO₂ and its carboxyl group to the N atom of formula I, R₁ is hydrogen, and R₂ is biphenyl,or its pharmaceutically acceptable non-toxic acid addition salts with inorganic or organic acids.
 30. Compounds of one of the formulas: ##STR188## wherein A is selected from the group consisting of L-phenylalanine, L-alanine, L-proline, L-valine, L-tryptophane and L-tyrosine moieties, where the N atom of the α-amino group which defines A as an amino acid is bound to SO₂ and its carboxyl group to the N atom of formula II, III or IV,R₁ is hydrogen, and R₂ is biphenyl, Y is F, Cl, Br, being the same or different, and n is 0, 1 or 2,or their pharmaceutically acceptable non-toxic acid addition salts with inorganic or organic acids.
 31. A pharmaceutical composition for inhibiting Ca²⁺ -dependent enzymes and proteins, the composition comprising compounds of the formula: ##STR189## wherein Z is phenyl, naphthyl, (5)- or (8)-isoquinolyl, possibly substituted by halogen;A is selected from the group consisting of L-phenylalanine, L-alanine, L-proline, L-valine, L-tryptophane and L-tyrosine moieties, where the N atom of the amino group which defines A as an α-amino acid is bound to SO₂ and its carboxyl group to the N atom of formula I R₁ is hydrogen, and R₂ is biphenyl,or their pharmaceutically acceptable non-toxic acid addition salts selected from the group consisting of the salts of inorganic acids in turn selected from the group consisting of hydrochloric acid, phosphoric acid and sulfuric acid; and the salts of organic acids in turn selected from the group consisting of citric acid, tartaric acid and methanesulfonic acid. 